A phase Ib study investigating the combination of everolimus and dovitinib in vascular endothelial growth factor refractory clear cell renal cancer

Powles, Thomas; Foreshew, Shah-Jalal Sarker; Shamash, Jonathan; Sarwar, Naveed; Crabb, Simon J.; Sahdev, Anju; Nixon, Jude; Lim, Louise; Pungaliya, Ashish; Foreshaw, Abigail; Davies, Rachel Bryant; Greenwood, Michelle; Wilson, Peter; Pacey, Simon; Galazi, Myra; Jones, Robert

doi:10.1016/j.ejca.2014.04.021

Cited by 17 publications

(10 citation statements)

References 11 publications

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“…First, targeting the FGF/FGF receptor pathway to reduce proliferation and potentially other oncogenic processes such as increased migratory activity in the tumor peripheral zone appears to be a promising approach. However, results from a limited number of clinical trials using FGF receptor or AKT inhibitors have not led to an integration of these compounds in clinical treatment algorithms [24][25][26].…”

Section: Discussionmentioning

confidence: 99%

Microenvironment-Derived FGF-2 Stimulates Renal Cell Carcinoma Cell Proliferation through Modulation of p27<sup>Kip1</sup>: Implications for Spatial Niche Formation and Functional Intratumoral Heterogeneity

et al. 2020

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Background/Objective: Clear cell renal cell carcinoma (ccRCC) is characterized by a high degree of functional intratumoral heterogeneity (ITH). This is highlighted by the finding that tumor cell proliferation and intracellular signaling occur preferentially in the tumor periphery. The driving forces for such a spatial organization are largely unknown. Herein, we investigate the role of the tumor microenvironment in the control of tumor cell proliferation and functional ITH. Methods: Conditioned media (CM) derived from nonmalignant peritumoral kidney tissue were used to stimulate RCC cells in vitro. A neutralization assay was used to characterize the role of FGF-2 in the CM. The molecular mechanisms underlying the action of CM on RCC cells were investigated us-ing immunoblotting, flow cytometry and immunofluorescence microscopy. Lastly, a series of ccRCCs were stained for Ki-67 and p27 Kip1 , and expression was analyzed in both tumor periphery and center. Results: We show that CM derived from nonmalignant kidney cells adjacent to an RCC can downregulate the expression of the CDK inhibitor p27 Kip1 through enhanced protein degradation in an FGF-2-dependent fashion. FGF-2 functions mainly through the PI3K/AKT pathway downstream of its receptors, and RCC cells with constitutively high AKT activity show not only an enhanced degradation of p27 Kip1 through the Emi1-Skp2 axis, but also a subcellular mislocalization of p27 Kip1 to the cytoplasmic compartment. Such a mislocalization was also detected in the tumor periphery in vivo suggesting that p27 Kip1 plays an important role in shaping this spatial niche. Conclusions: Our results suggest that the tumor microenvironment is involved in shaping the tumor peripheral niche by stimulating the enhanced proliferation that is characteristic for this zone.

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Section: Discussionmentioning

confidence: 99%

Microenvironment-Derived FGF-2 Stimulates Renal Cell Carcinoma Cell Proliferation through Modulation of p27<sup>Kip1</sup>: Implications for Spatial Niche Formation and Functional Intratumoral Heterogeneity

et al. 2020

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“…Foretinib or GSK1363089 was originally discovered by Exelixis and is currently under investigation by GlaxoSmithKline for various disease indications, such as RCC, GIST, HCC, NSCLC, breast and head and neck cancer [139,140]. As a multikinase inhibitor, its inhibitory activity has been known to be directed especially against VEGFR and MET, further against RON, AXL, Tie-2, c-KIT, Flt-3 and PDGFR.…”

Section: Foretinibmentioning

confidence: 98%

“…Dovitinib plasma concentrations resulted in an increase when compared to dovitinib intake alone [139].…”

Section: Ddismentioning

confidence: 99%

Pharmacokinetic Aspects of Vascular Endothelial Growth Factor Tyrosine Kinase Inhibitors

2015

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Scientists have identified the impact of angiogenesis on tumor growth and survival. Among other efficient drugs, several small-molecule tyrosine kinase inhibitors (TKIs) targeting the vascular endothelial growth factor receptor (VEGFR) have been developed and have already been integrated into the treatment of various advanced malignancies. This review provides a compilation of current knowledge on the pharmacokinetic aspects of all VEGFR-TKIs already approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) and of those still under investigation. Additional information on substance metabolism, potential for drug-drug interactions (DDIs), and the need for dose adaptation in patients with predominant renal and/or hepatic impairment has been included. All TKIs introduced in this review were administered orally, allowing for easy drug handling for healthcare professionals and patients. For almost all substances, the maximum plasma concentrations were reached within a short period of time. The majority of the substances showed a high plasma protein binding and their excretion occurred via the feces and, to a lesser extent, via the urine. In most cases, dose adaptation in patients with mild to moderate renal or hepatic impairment is not recommended. Cytochrome P450 (CYP) 3A4 was found to play a crucial role in the drug metabolic processes of many compounds. In order to prevent unwanted DDIs, co-administration of VEGFR TKIs together with CYP3A4 inhibitors or inducers should be avoided. Throughout all TKIs, the data indicate high inter-individual variability. The causes of this are still unclear and require further research to allow for individualization of treatment regimens.

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“…A phase Ib 18 patients study was conducted by Powles et al [20]. They found that Everolimus (an mTOR inhibitor) and dovitinib present activity in metastatic clear cell RCC.…”

Section: Dovitinibmentioning

confidence: 99%

Newly-presented potential targeted drugs in the treatment of renal cell cancer

Zhang

Zheng

2016

Open Life Sciences

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Renal cell carcinoma (RCC) is the most frequent form of renal cancer, and is associated with a high frequency of metastasis. While, there is few therapeutic methods can substantially prolong survival. Superior to cytokine therapy with IL-2 and/or IFN-α, several newer targeted treatments are available for the treatment of patients with advanced conventional (clear cell) renal cell carcinoma (RCC), which received improved outcomes. These newer targeted treatments include the multi-targeted tyrosine kinase inhibitors (TKIs, sorafenib, sunitinib, pazopanib, and axitinib), the humanised antivascular endothelial growth factor (VEGF) monoclonal antibody [bevacizumab combined with interferon (IFN)-α], and mTOR (mammalian target of rapamycin) complex 1 kinase inhibitors (everolimus and temsirolimus). However, these targeted drugs are still associated with limited efficacy and high toxicity, so there is still a strong need for further discovery of new targeted drugs. In the present manuscript, we summarize newly-presented potential targeted drugs for RCC, classified by drug characteristic, small molecule, small molecule combination, monoclonal antibody, polysaccharides, organometals and peptides.

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A phase Ib study investigating the combination of everolimus and dovitinib in vascular endothelial growth factor refractory clear cell renal cancer

Cited by 17 publications

References 11 publications

Microenvironment-Derived FGF-2 Stimulates Renal Cell Carcinoma Cell Proliferation through Modulation of p27<sup>Kip1</sup>: Implications for Spatial Niche Formation and Functional Intratumoral Heterogeneity

Microenvironment-Derived FGF-2 Stimulates Renal Cell Carcinoma Cell Proliferation through Modulation of p27<sup>Kip1</sup>: Implications for Spatial Niche Formation and Functional Intratumoral Heterogeneity

Pharmacokinetic Aspects of Vascular Endothelial Growth Factor Tyrosine Kinase Inhibitors

Newly-presented potential targeted drugs in the treatment of renal cell cancer

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